Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

Antidepressant agents are indispensable in treating severe depression. Since their discovery in the 1950s, adverse effect profiles of these drugs have been improved, whereas clinical efficacy is still unsatisfactory because 1 in 3 patients does not fully recover from depression, even after several treatment trials.^1,2 Genetic factors contribute to the general variability in drug response^3,4 and, according to family studies,^5-7 this is the case for antidepressant agents, which suggests that the individual genetic profile may provide guidance in medication selection.⁸ Up to now, pharmacogenetic studies have focused on candidate genes implicated in the mechanisms of antidepressant drug action or in the pharmacokinetics of such drugs. For example, an insertion-deletion polymorphism in the promoter region of the serotonin transporter gene (SLC6A4) seems to predict response to selective serotonin reuptake inhibitors,⁹ potentially mediated by differences in selective serotonin reuptake inhibitor tolerability,¹⁰ and a variation in the ABCB1 gene coding for a P-glycoprotein that determines brain tissue penetration of many antidepressant drugs may predict clinical outcome in patients treated with substrates of this blood-brain barrier regulation molecule.¹¹ Several studies reported that variants of a gene coding for FKBP5,^12-14 a co-chaperone involved in stress hormone signaling, and variants for 5HT2A¹⁵ are predictive of treatment response but do not effectively guide treatment selection. Further associations have been reported for the glutamatergic receptor gene GRIK4,¹⁶ the enzymatic gene PDER11A,¹⁷ inflammation-related genes (CD3E, PRKCH, PSMD9, and STAT3),¹⁸ and UCN3¹⁸ expressing a ligand of the CRF2 receptor.